- Open Access
Resveratrol: a supplementation for men or for mice?
© Ponzo et al.; licensee BioMed Central Ltd. 2014
Received: 20 May 2014
Accepted: 20 May 2014
Published: 3 June 2014
Resveratrol is a polyphenolic compound found in several plants. In the last decades, the interest in this compound has enormously increased after benefits on metabolism and increased lifespan of various organisms have been reported with its supplementation. Several in-vitro and animal studies have observed that resveratrol can act on multiple molecular targets, including sirtuins, a class of NAD + -dependent deacetylases. Despite the enthusiastic results reported in many animal- and in-vitro studies, few trials have been performed in humans with contrasting results. These conflicting data may be due at least in part to differences in the characteristics of the patients enrolled, the dosages and the duration of supplementation. Furthermore, many questions remain still unsolved, such as the dose or the duration of treatment to maximize its effects, the bioavailability of resveratrol and the role of food matrix to improve its bioactivity.
In conclusion, at present the use of resveratrol as a supplement is not yet justified by the existing evidence.
Resveratrol owes its fame to the so-called "French Paradox". In the early 90s, the term derived from the observation that the French adults showed a relatively low incidence of coronary heart disease in comparison to the corresponding-age individuals from other Western countries, despite a high dietary intake of saturated fatty acids. The French scientist Renaud attributed this paradox to the increased consumption of red wine and, later, the high resveratrol content of wine has been identified as one of the potential mechanisms of the benefits of red wine. From that moment, the interest in this natural compound has grown enormously. Research has thereafter shifted from human to animal models and the number of studies on resveratrol has increased extraordinarily since 1997, when its anti-cancer properties have been reported. Several authors have investigated the hypothetical cardioprotective, anti-cancer, anti-inflammatory and antioxidant properties of resveratrol. A long list of beneficial effects and many possible direct or indirect molecular targets and mechanisms of action of resveratrol have been described in animal and in vitro studies. Only recently, research has focused on humans again, and so far a number of human clinical trial have been conducted.
A milestone in resveratrol research came in the early 2000s when some authors reported that resveratrol is able to mimic caloric restriction effects and increased yeast, worms, flies and rodents lifespan[5, 6]. This effect was ascribed to the resveratrol ability to activate sirtuin proteins, NAD +-dependent de-acetylase involved in the regulation of metabolism, apoptosis, mitochondrial biogenesis, inflammation, fatty acid metabolism, and glucose homeostasis[7–10]. But sirtuins are not the only target of resveratrol and thanks to its ability to act on numerous molecular targets, resveratrol exhibits versatile biological effects: from the inhibition of angiogenesis, cancer cell and metastatic cell growth[11–24] to the improvement of vascular function, arterial blood pressure values, and platelet aggregation[25–27], and the anti-inflammatory[28, 29], antioxidant[30, 31] and hypoglycaemic effects[32–38].
To date, the human clinical trials available have shown conflicting or controversial results about the anticancer, cardioprotective and anti-inflammatory properties of resveratrol[39–50]. Other sources of controversy derive from the fact that many of the hypothesized mechanisms have not yet been demonstrated in humans. However, some positive results have been found. A recent meta-analysis of 11 human clinical trials, investigating the effects of resveratrol on the metabolic pattern of type 2 diabetic patients, points out a beneficial effect of resveratrol consumption on fasting glucose and glycosylated haemoglobin values, and insulin resistance measured by the homeostatic model assessment.
Why have not all the promising results found in preclinical studies been confirmed in humans?
Differences in formulation, dosage of resveratrol and duration of follow-up may at least in part justify these conflicting results. However, many other issues remain unresolved. For example, the dose of resveratrol to maximize its effects without safety concerns is still unknown; similarly the duration of supplementation remains a matter of concern (a high dose for a short-term or a low dose for a long period?). Moreover, the relationship between the low bioavailability and the high bioactivity of resveratrol, the so-called resveratrol paradox, has not yet been solved. Since this molecule is rapidly metabolized and its concentrations quickly disappear in the blood, it is difficult to justify its benefits, while the knowledge of metabolites or mediators responsible for the effects of resveratrol is still scanty.
The majority of trans-resveratrol metabolites were found to be derived by glucuronidation or sulfation. Since the rapid metabolism seems to be one of the major reasons for the lower effect on humans, a part of the research is focusing on how to improve the bioavailability of resveratrol. One way to improve the bioavailability may be the combination of resveratrol with other agents that inhibit its metabolism in vivo. Studies have shown that natural compounds, including quercetin and piperine (an alkaloid derived from black pepper), can inhibit glucuronidation and sulfation of resveratrol[53–55]. However, further studies are needed to assess whether these combinations may determine an increase in its bioavailability.
The role of resveratrol in an "epigenetic diet", a diet with a potential impact in delaying ageing and preventing age-related diseases, could be a further topic worthy of investigation.
Finally, another interesting but unsolved topic is the possible influence of the food matrix on the bioavailability of resveratrol in humans. Some authors have shown that trans-resveratrol is better absorbed when assumed through wine or grape juice than from tablets; in vivo bioavailability and bioactivity could be increased by the food matrix because of the presence of other natural compounds, such as other polyphenols that seem to play a synergic role and increase resveratrol bioactivity.
The versatile properties of resveratrol found in in-vitro and animal studies have not been unequivocally confirmed in human studies. At present, resveratrol should be assumed by natural foods, mainly through the moderate consumption of red wine, grape juice or peanuts, while the consumption as a supplement is not justify by the existing scientific literature. Many issues remain certainly open, and a resveratrol formulation with increased bioavailability and effective in humans as in mice has yet to be discovered.
- Scalbert A, Williamson G: Dietary intake and bioavailability of polyphenols. J Nutr. 2000, 130: 2073S-2085S.PubMedGoogle Scholar
- Burns J, Yakota T, Ashihara H, Lean MEJ, Crozier A: Plant foods and herbal sources of resveratrol. J Agric Food Chem. 2002, 50: 3337-3340. 10.1021/jf0112973.View ArticlePubMedGoogle Scholar
- Renaud S, de Lorgeril M: Wine, alcohol, platelets, and the French paradox for coronary heart disease. Lancet. 1992, 339: 1523-1526. 10.1016/0140-6736(92)91277-F.View ArticlePubMedGoogle Scholar
- Jang M, Cai L, Udeani GO, Slowing KV, Thomas CF, Beecher CW, Fong HH, Farnsworth NR, Kinghorn AD, Mehta RG, Moon RC, Pezzuto JM: Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science. 1997, 275: 218-220. 10.1126/science.275.5297.218.View ArticlePubMedGoogle Scholar
- Baur JA, Pearson KJ, Price NL: Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 2006, 444: 337-342. 10.1038/nature05354.View ArticlePubMedGoogle Scholar
- Howitz KT, Bitterman KJ, Cohen HT: Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature. 2003, 425: 191-196. 10.1038/nature01960.View ArticlePubMedGoogle Scholar
- Lagouge M, Argmann C, Gehart-Hines Z: Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PRG-1. Cell. 2006, 127: 1-14.View ArticleGoogle Scholar
- Csiszar A, Labinskyy N, Pinto JT, Ballabh P, Zhang HR, Losonczy G, Pearson K, de Cabo R, Pacher P, Zhang CH, Ungvari Z: Resveratrol induces mitochondrial biogenesis in endothelial cells. Am J Physiol Heart Circ Physiol. 2009, 297: H13-H20. 10.1152/ajpheart.00368.2009.PubMed CentralView ArticlePubMedGoogle Scholar
- Kao CL, Chen LK, Chang YL, Yung MC, Hsu CC, Chen YC, Lo WL, Chen SJ, Ku HH, Hwang SJ: Resveratrol protects human endothelium from H2O2-induced oxidative stress and senescence via Sirt1 activation. J Atheroscler Thromb. 2010, 17: 970-979. 10.5551/jat.4333.View ArticlePubMedGoogle Scholar
- Wang GL, Fu YC, Xu WC, Feng YQ, Fang SR, Zhou XH: Resveratrol inhibits the expression of SREBP1 in cell model of steatosis via Sirt1-FOXO1 signaling pathway. Biochem Biophys Res Commun. 2009, 380: 644-649. 10.1016/j.bbrc.2009.01.163.View ArticlePubMedGoogle Scholar
- Shankar S, Singh G, Srivastava RK: Chemoprevention by resveratrol: molecular mechanisms and therapeutic potential. Front Biosci. 2007, 12: 4839-4854. 10.2741/2432.View ArticlePubMedGoogle Scholar
- Aziz MH, Kumar R, Ahmad N: Cancer chemoprevention by resveratrol: in vitro and in vivo studies and the underlying mechanisms. Int J Oncol. 2003, 23: 17-28.PubMedGoogle Scholar
- Aziz MH, Nihal M, Fu VX, Jarrard DF, Ahmad N: Resveratrol-caused apoptosis of human prostate carcinoma LNCaP cells is mediated via modulation of phosphatidylinositol 3_-kinase/Akt pathway and Bcl-2 family proteins. Mol Cancer Ther. 2006, 5: 1335-1341. 10.1158/1535-7163.MCT-05-0526.View ArticlePubMedGoogle Scholar
- Reagan-Shaw S, Afaq F, Aziz MH, Ahmad N: Modulations of critical cell cycle regulatory events during chemoprevention of ultraviolet B mediated responses by resveratrol in SKH-1 hairless mouse skin. Oncogene. 2004, 23: 5151-5160. 10.1038/sj.onc.1207666.View ArticlePubMedGoogle Scholar
- Lee HS, Ha AW, Kim WK: Effect of resveratrol on the metastasis of 4 T1 mouse breast cancer cells in vitro and in vivo. Nutr Res Pract. 2012, 6: 294-300. 10.4162/nrp.2012.6.4.294.PubMed CentralView ArticlePubMedGoogle Scholar
- Atten MJ, Godoy-Romero E, Attar BM, Milson T, Zopel M, Holian O: Resveratrol regulates cellular PKC alpha and delta to inhibit growth and induce apoptosis in gastric cancer cells. Invest New Drugs. 2005, 23: 111-119. 10.1007/s10637-005-5855-8.View ArticlePubMedGoogle Scholar
- Huderson AC, Myers JN, Niaz MS, Washington MK, Ramesh A: Chemoprevention of benzo(a)pyrene-induced colon polyps in Apc(Min)mice by resveratrol. J Nutr Biochem. 2012, 24: 713-724.PubMed CentralView ArticlePubMedGoogle Scholar
- Juan ME, Alfaras I, Planas JM: Colorectal cancer chemoprevention by trans-resveratrol. Pharmacol Res. 2012, 65: 584-591. 10.1016/j.phrs.2012.03.010.View ArticlePubMedGoogle Scholar
- Patel KR, Brown VA, Jones DJ, Britton RG, Hemingway D, Miller AS, West KP, Booth TD, Perloff M, Crowell JA, Brenner DE, Steward WP, Gescher AJ, Brown K: Clinical pharmacology of resveratrol and its metabolites in colorectal cancer patients. Cancer Res. 2010, 70: 7392-7399. 10.1158/0008-5472.CAN-10-2027.PubMed CentralView ArticlePubMedGoogle Scholar
- Athar M, Back JH, Tang X, Kim KH, Kopelovich L, Bickers DR, Kim AL: Resveratrol: a review of preclinical studies for human cancer prevention. Toxicol Appl Pharmacol. 2007, 224: 274-283. 10.1016/j.taap.2006.12.025.PubMed CentralView ArticlePubMedGoogle Scholar
- Malhotra A, Nair P, Dhawan DK: Curcumin and resveratrol synergistically stimulate p21 and regulate cox-2 by maintaining adequate zinc levels during lung carcinogenesis. Eur J Cancer Prev. 2011, 20: 411-416. 10.1097/CEJ.0b013e3283481d71.View ArticlePubMedGoogle Scholar
- Howells LM, Berry DP, Elliott PJ, Jacobson EW, Hoffmann E, Hegarty B, Brown K, Steward WP, Gescher AJ: Phase I randomized, doubleblind pilot study of micronized resveratrol (SRT501) in patients with hepatic metastases—safety, pharmacokinetics, and pharmacodynamics. Cancer Prev Res. 2011, 4: 1419-1425. 10.1158/1940-6207.CAPR-11-0148.View ArticleGoogle Scholar
- Vang O, Ahmad N, Baile CA, Baur JA, Brown K, Csiszar A, Das DK, Delmas D, Gottfried C, Lin HY, Ma QY, Mukhopadhyay P, Nalini N, Pezzuto JM, Richard T, Shukla Y, Surh YJ, Szekeres T, Szkudelski T, Walle T, Wu JM: What is new for an old molecule? Systematic review and recommendations on the use of resveratrol. PLoS One. 2011, 6: e19881-10.1371/journal.pone.0019881.PubMed CentralView ArticlePubMedGoogle Scholar
- Salado C, Olaso E, Gallot N, Valcarcel M, Egilegor E, Mendoza L, Vidal-Vanaclocha F: Resveratrol prevents inflammation-dependent hepatic melanoma metastasis by inhibiting the secretion and effects of interleukin-18. J Transl Med. 2011, 9: 59-10.1186/1479-5876-9-59.PubMed CentralView ArticlePubMedGoogle Scholar
- Wu JM, Hsieh TC: Resveratrol: a cardioprotective substance. Ann N Y Acad Sci. 2011, 1215: 16-21. 10.1111/j.1749-6632.2010.05854.x.View ArticlePubMedGoogle Scholar
- Wang H, Yang YJ, Qian HY, Zhang Q, Xu H, Li JJ: Resveratrol in cardiovascular disease: what is known from current research?. Heart Fail Rev. 2012, 17: 437-448. 10.1007/s10741-011-9260-4.View ArticlePubMedGoogle Scholar
- Tomé-Carneiro J, Larrosa M, González-Sarrías A, Tomás-Barberán FA, García-Conesa MT, Espín JC: Resveratrol and clinical trials: the crossroad fromin vitro studies to human evidence. Curr Pharm Des. 2013, 19: 6064-6093. 10.2174/13816128113199990407.PubMed CentralView ArticlePubMedGoogle Scholar
- Manna SK, Mukhopadhyay A, Aggarwal BB: Resveratrol suppresses TNFinduced activation of nuclear transcription factors NF-B, activator protein-1, and apoptosis: potential role of reactive oxygen intermediates and lipid peroxidation. J Immunol. 2000, 164: 6509-6519. 10.4049/jimmunol.164.12.6509.View ArticlePubMedGoogle Scholar
- Holmes MM, Baldwin ASJ: Chemopreventive properties of trans-resveratrol are associated with inhibition of activation of the IB kinase. Cancer Res. 2000, 60: 3477-3483.Google Scholar
- Rocha KKR, Souza GA, Ebaid GX, Seiva FRF, Cataneo AC, Novelli ELB: Resveratrol toxicity: effects on risk factors for atherosclerosis and hepatic oxidative stress in standard and high-fat diets. Food Chem Toxicol. 2009, 47: 1362-1367. 10.1016/j.fct.2009.03.010.View ArticlePubMedGoogle Scholar
- Li Y, Cao Z, Zhu H: Upregulation of endogenous antioxidants and phase 2 enzymes by the red wine polyphenol, resveratrol in cultured aortic smooth muscle cells leads to cytoprotection against oxidative and electrophilic stress. Pharmacol Res. 2006, 53: 6-15. 10.1016/j.phrs.2005.08.002.View ArticlePubMedGoogle Scholar
- Su HC, Hung LM, Chen JK: Resveratrol, a red wine antioxidant, possesses an insulin-like effect in streptozotocin-induced diabetic rats. Am J Physiol Endocrinol Metab. 2006, 290: E1339-1346. 10.1152/ajpendo.00487.2005.View ArticlePubMedGoogle Scholar
- Palsamy P, Subramanian S: Ameliorative potential of resveratrol on proinflammatory cytokines, hyperglycemia mediated oxidative stress, and pancreatic beta-cell dysfunction in streptozotocin-nicotinamide-induced diabetic rats. J Cell Physiol. 2010, 224: 423-432. 10.1002/jcp.22138.View ArticlePubMedGoogle Scholar
- Palsamy P, Subramanian S: Resveratrol, a natural phytoalexin, normalizes hyperglycemia in streptozotocin-nicotinamide induced experimental diabetic rats. Biomed Pharmacother. 2008, 62: 598-605.View ArticlePubMedGoogle Scholar
- Timmers S, Konings E, Bilet L, Houtkooper RH, van de Weijer T, Goossens GH, Hoeks J, van der Krieken S, Ryu D, Kersten S: Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metab. 2011, 14: 612-622. 10.1016/j.cmet.2011.10.002.View ArticlePubMedGoogle Scholar
- Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F, Messadeq N, Milne J, Lambert P, Elliott P: Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell. 2006, 127: 1109-1122. 10.1016/j.cell.2006.11.013.View ArticlePubMedGoogle Scholar
- Penumathsa SV, Thirunavukkarasu M, Zhan L, Maulik G, Menon VP, Bagchi D, Maulik N: Resveratrol enhances GLUT-4 translocation to the caveolar lipid raft fractions through AMPK/Akt/eNOS signaling pathway in diabetic myocardium. J Cell Mol Med. 2008, 12: 2350-2361. 10.1111/j.1582-4934.2008.00251.x.PubMed CentralView ArticlePubMedGoogle Scholar
- Chi TC, Chen WP, Chi TL, Kuo TF, Lee SS, Cheng JT, Su MJ: Phosphatidylinositol-3-kinase is involved in the antihyperglycemic effect induced by resveratrol in streptozotocin-induced diabetic rats. Life Sci. 2007, 80: 1713-1720. 10.1016/j.lfs.2007.02.002.View ArticlePubMedGoogle Scholar
- Tomé-Carneiro J, Gonzálvez M, Larrosa M, Yáñez-Gascón MJ, García-Almagro FJ, Ruiz-Ros JA, Tomás-Barberán FA, García-Conesa MT, Espín JC: Resveratrol in primary and secondary prevention of cardiovascular disease: a dietary and clinical perspective. Ann N Y Acad Sci. 2013, 1290: 37-51. 10.1111/nyas.12150.View ArticlePubMedGoogle Scholar
- Sahebcar A: Effects of resveratrol supplementation on plasma lipids: a systematic review and meta-analysis of randomized controlled trials. Nutr Rev. 2013, 71: 822-835. 10.1111/nure.12081.View ArticleGoogle Scholar
- Ghanim H, Sia CL, Abuaysheh S, Korzeniewski K, Patnaik P, Marumganti A, Chaudhuri A, Dandona P: An antiinflammatory and reactive oxygen species suppressive effects of an extract of Polygonum cuspidatum containing resveratrol. J Clin Endocrinol Metab. 2010, 95: E1-E8. 10.1210/jc.2010-0482.PubMed CentralView ArticlePubMedGoogle Scholar
- Bo S, Ciccone G, Castiglione A, Gambino R, De Michieli F, Villois P, Durazzo M, Cavallo-Perin P, Cassader M: Antiinflammatory and Antioxidant Effects of Resveratrol in Healthy Smokers. Curr Med Chem. 2012, 20: 1323-1331.View ArticleGoogle Scholar
- Poulsen MM, Vestergaard PF, Clasen BF, Radko Y, Christensen LP, Stødkilde-Jørgensen H, Møller N, Jessen N, Pedersen SB, Jørgensen JO: High-Dose Resveratrol Supplementation in Obese Men: An Investigator-Initiated, Randomized, Placebo-Controlled Clinical Trial of Substrate Metabolism, Insulin Sensitivity, and Body Composition. Diabetes. 2012, 62: 1186-1195.View ArticlePubMedGoogle Scholar
- Yoshino J, Conte C, Fontana L, Mittendorfer B, Imai S, Schechtman KB, Gu C, Kunz I, Rossi Fanelli F, Patterson BW, Klein S: Resveratrol supplementation does not improve metabolic function in nonobese women with normal glucose tolerance. Cell Metab. 2012, 16: 658-664. 10.1016/j.cmet.2012.09.015.PubMed CentralView ArticlePubMedGoogle Scholar
- Crandall JP, Oram V, Trandafirescu G, Reid M, Kishore P, Hawkins M, Cohen HW, Barzilai N: Pilot Study of resveratrol in Older Adults With Impaired Glucose Tolerance. J Gerontol A Biol Sci Med Sci. 2012, 67: 1307-1312. 10.1093/gerona/glr235.PubMed CentralView ArticlePubMedGoogle Scholar
- Fujitaka K, Otani H, Jo F, Jo H, Nomura E, Iwasaki M, Nishikawa M, Iwasaka T, Das DK: Modified resveratrol Longevinex improves endothelial function in adults with metabolic syndrome receiving standard treatment. Nutr Res. 2011, 31: 842-847. 10.1016/j.nutres.2011.09.028.View ArticlePubMedGoogle Scholar
- Tomé-Carneiro J, Gonzálvez M, Larrosa M, Yáñez-Gascón MJ, Garcìa-Almagro FJ, Ruiz-Ros JA, Garcìa-Conesa MT, Tomàs-Barbéran FA, Espìn JC: One-year consumption of a grape nutraceutical containing resveratrol improves the inflammatory and fibrinolytic status of patients in primary prevention of cardiovascular disease. Am J Cardiol. 2012, 110: 356-363. 10.1016/j.amjcard.2012.03.030.View ArticlePubMedGoogle Scholar
- Magyar K, Halmosi R, Palfi A, Feher G, Czopf L, Fulop A, Battyany I, Sumegi B, Toth K, Szabados E: Cardioprotection by resveratrol: A human clinical trial in patients with stable coronary artery disease. Clin Hemorheol Microcirc. 2012, 50: 179-187.PubMedGoogle Scholar
- Heger A, Ferk F, Nersesyan A, Szekeres T, Kundi M, Wagner KH, Haidinger G, Misik M, Knasmuller S: Intake of a resveratrol- containing dietary supplement has no impact on DNA stability in healthy subjects. Mutat Res. 2012, 749: 82-86. 10.1016/j.mrgentox.2012.07.005.View ArticlePubMedGoogle Scholar
- Militaru C, Donoiu I, Craciun A, Scorei ID, Bulearca AM, Scorei RI: Oral resveratrol and calcium fructoborate supplementation in subjects with stable angina pectoris: Effects on lipid profiles, inflammation markers, and quality of life. Nutrition. 2013, 29: 178-183. 10.1016/j.nut.2012.07.006.View ArticlePubMedGoogle Scholar
- Liu K, Zhou R, Wang B, Mi MT: Effect of resveratrol on glucose control and insulin sensitivity: a meta-analysis of 11 randomized controlled trials. Am J Clin Nutr. in pressGoogle Scholar
- Walle T: Bioavailability of resveratrol. Ann N Y Acad Sci. 2011, 1215: 9-15. 10.1111/j.1749-6632.2010.05842.x.View ArticlePubMedGoogle Scholar
- de Santi C, Pietrabissa A, Mosca F, Pacifici GM: Glucuronidation of resveratrol, a natural product present in grape and wine, in the human liver. Xenobiotica. 2000, 30: 1047-1054. 10.1080/00498250010002487.View ArticlePubMedGoogle Scholar
- De Santi C, Pietrabissa A, Spisni R, Mosca F, Pacifici GM: Sulphation of resveratrol, a natural product present in grapes and wine, in the human liver and duodenum. Xenobiotica. 2000, 30: 609-617. 10.1080/004982500406435.View ArticlePubMedGoogle Scholar
- Johnson JJ, Nihal M, Siddiqui IA, Scarlett CO, Bailey HH, Mukhtar H, Ahmad N: Enhancing the bioavailability of resveratrol by combining it with piperine. Mol Nutr Food Res. 2011, 55: 1169-1176. 10.1002/mnfr.201100117.PubMed CentralView ArticlePubMedGoogle Scholar
- Ortuño J, Covas MI, Farre M, Pujadas M, Fito M, Khymenets O, Andres- Lacueva C, Roset P, Joglar J, Lamuela-Raventos RM, de la Torre R: Matrix effects on the bioavailability of resveratrol in humans. Food Chem. 2010, 4: 1123-1130.View ArticleGoogle Scholar
- Scheepens A, Tan K, Paxton JW: Improving the oral bioavailability of beneficial polyphenols through designed synergies. Genes Nutr. 2010, 5: 75-87. 10.1007/s12263-009-0148-z.PubMed CentralView ArticlePubMedGoogle Scholar
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